3,5-Dinitroaniline derivatives

ABSTRACT

Compounds of the formula:   wherein R1 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or sec-butyl, R2 represents hydrogen or alkyl of 1 through 4 carbon atoms or cycloalkyl of 3 or 4 carbon atoms, and R3 represents hydrogen, methyl or ethyl, all of which are novel except for three compounds, have been found to be of use in the prevention of coccidiosis in chickens.

United States Patent [1 1 Sharp et al.

[4 1 Oak], 1975 3,5-DlNlTROANlLINE DERIVATIVES [73] Assignee: May &Baker Limited, England [22] Filed: Mar. 21, I974 [2|] Appl. No: 453,643

[30] Foreign Application Priority Data Mar. 23, 1973 United Kingdoml4l9l/73 [52] US. Cl. .1 260/562 R; 424/324 [5|] Int. Cl. C07C l03/l27[58] Field of Search 260/562 R [56] References Cited UNITED STATESPATENTS 3,015,606 l/l962 Walde 424/324 3,] [9,736 l/I964 Clark et al..260/562 R 3,l49,(132 9/1964 Waring 260/526 R 3,4l8,345 12/1968 Baker .4260/526 R OTHER PUBLICATIONS Duffy et al., Nature, 178, (1956), pp.l242l243,

Primary ExaminerArthur P. Demers Attorney, Agent, or FirmStevens, Davis,Miller & Mosher [57] ABSTRACT Compounds of the formula:

R' con N wherein R' represents hydrogen, methyl, ethyl, npropyl,iso-propyl, nbutyl, iso-butyl or sec-butyl, R represents hydrogen oralkyl of I through 4 carbon atoms or cycloalkyl of 3 or 4 carbon atoms,and R represents hydrogen, methyl or ethyl, all of which are novelexcept for three compounds, have been found to be of use in theprevention of coccidiosis in chickens,

12 Claims, N0 Drawings 1 3,5-DINITROANILINE DERIVATIVES This inventionrelates to dinitroaniline derivatives which are of use in the preventionof coccidiosis in chickens.

Coccidiosis, a disease caused by infections by protozoan parasites ofthe genus Eimeria, is one of the most important potential causes ofeconomic loss in chicken flocks, particularly those raised underintensive conditions. The disease has a world-wide incidence and mayoccur wherever poultry are reared, and, if left untreated, often causesextensive loss of fowl. Economic loss results not onlyfrom mortality ofthe infected birds but also morbidity which may manifest itself indepression of body growth rate, reduction of food conversion efficiencyand a general deterioration which is found in the carcass at slaughter.The elimination or control of coccidiosis is, therefore. of the utmostimportance in successful chicken raising. Although other species occurin the chicken, the following five species of Eimeria, namely E.renella, E. acervulina, E. necalrix, E. bruneni and E. maxima, aregenerally regarded as being responsible for the economic losses due tococciodiosis in the rearing of chickens.

Infections with E. tenella, which is responsible for a severe infectionof the caecum of chickens, and E. net-atria: frequently result inmortality while infections due to the other three species are lessfrequently the cause of mortality but nevertheless result in economicloss due to depression of growth rate, feed-conversion efficiency andcarcass deterioration. E. renella and E. necatrix have generally beenregarded in the past as being the most important species and efforts inthe selection of anti-coccidial agents have been directed primarilytowards the control of these species. In recent years it has been found,however, that while the control of E. Ienella and E. necarrix remains animportant problem, the incidence of disease caused by E. acervulina, E.maxima and E. bruneni has increased, thereby increasing the importanceof their control.

An additional problem, which is encountered in the control ofcoccidiosis and is of increasing importance, is the emergence of strainsof Eimeria which are resistant to anticoccidial agents which normallycontrol the species in question,

This problem of resistance has been found to a greater or lesser extentwith all anti-coccidial agents which have been used commercially on awide scale and may arise from severe infection challenges and theselection of inherently more resistant coccidia by the control of moresusceptible organisms by the anticoccidial agents.

In addition to controlling the disease, it is naturally important thatan anti-coccidial agent should be well tolerated at dose levels whichare used and should have no adverse effect upon the health of the birdsto which it is administered. As a result of research andexperimentation, it has been found that 3,5-dinitroaniline derivativesof the general formula:

R' COR NO, NO,

wherein R represents a hydrogen atom or a methyl, ethyl, n-propy],iso-propyl, n-butyl, iso-butyl or secbutyl group, R represents ahydrogen atom, a straightor branched-chain alkyl group containing from Ito 4 carbon atoms or a cycloalkyl group containing 3 or 4 carbon atoms,and R represents a hydrogen atom or a methyl or ethyl group, possessuseful activity against Eimeria, particularly Eimeria tenella andEimeria acervulina, infections of chickens and are useful in theprevention of coccidiosis in chickens.

Compounds of special value in this respect are those compounds offormula I wherein R and R represent hydrogen atoms while R represents ahydrogen atom or a methyl, ethyl or isopropyl group and those compoundsof formula I wherein R represents a hydrogen atom and R represents amethyl group while R represents a methyl or ethyl group, that is to sayindividual compounds of particular importance are 3',5-dinitroacetanilide, 3 ',5 '-dinitro-N-ethylacetanilidc,3',5'-dinitroformanilide, 3',5'-dinitropropionanilide,3,5-dinitro-iso-butyranilide and, more especially, 3,-5'-dinitro-N-methylacetanilide.

According to the present invention there is provided a method for theprevention of coccidiosis in chickens, more particularly coccidiosiscaused by infections of Eimeria tenellu and Eimeria acervulina, whichcomprises administering to the birds a prophylacticallyeffective amountof one or more of the compounds of general formula 1. According to apreferred embodiment, the compounds of general formula I areadministered in the diet of chickens in an amount equal to between0.0025 percent and 0.05 percent, preferably between 0.00625 percent and0.025 percent, by weight of the food consumed.

According to a feature of the present invention there are providedveterinary compositions useful for the prevention of coccidiosis inchickens, comprising one or more of the compounds of formula I, asactive ingredient, in association with a physiologically innocuouscarrier (i.e. a carrier which is not harmful to the chickens at thedosages used) which may be solid, semi-solid or a liquid. Suchcompositions are conveniently produced by intimately dispersing theactive ingredient through the carrier, if necessary, where the carrieris a liquid in which the active ingredient is but sparingly soluble,e.g. water, using an emulsifying, dispersing, suspending or wettingagent.

Preferred compositions are solids or semi-solids in which the carrier isprovided at least in part by a chicken feedstuff, i.e. an organic ormineral substance which is intended to be fed to the chicken; that is tosay, the active ingredient may be incorporated in a solid or semi-solidfeedstuff. Incorporation of the active ingredient in the feedstuff,which may be a commercial starter, grower, layer or breeder feed, may beeffected by any conventional method such as stirring, tumbling orgrinding. Compositions of varying concentrations can be prepared byaltering the ratio of carrier to active ingredient. The activeingredient may also be incorporated in the feedstuff in the form of apowder concentrate containing active ingredient and a solid,physiologically innocuous carrier, e.g. wheat middlings, talc, kaolin orchalk or a diatomaceous earth, such as kieselguhr, or a mixture thereof,and such compositions are also included within the scope of thisinvention. These compositions may also contain agents to promoteadhesion of the active ingredient to the carrier, for example soya oil.To the active ingredient or powders containing it, there may be addedbefore admixture with the feedstuff, one or more physiologicallyinnocuous wetting and/or dispersing agents, for example, thecondensation product of Bmaphthalenesulphonic acid and formaldehyde,sodium lauryl sulphate or polyoxyethylenc( )sorbitan monooleate.Alternatively, when a wetting, suspending, emulsifying or dispersingagent is added to the active ingredient or powder, the compositions soobtained may be mixed with water to provide stable dispersions suitablefor addition to feedstuffs.

Compositions suitable for addition to feedstuffs which comprise theactive ingredient in association with a wetting, suspending, dispersingor emulsifying agent, with or without a physiologically innocuouscarrier, are also included within the scope of this invention.

Liquid compositions may be dispersions of the active ingredient indrinking water, and these compositions may be prepared from concentrateswhich may be added to water, or are self-emulsifying with water. Suchconcentrates comprise the active ingredient in association with one ormore wetting, suspending, dispersing, emulsifying, thickening or gellingagents, with or without a physiologically innocuous carrier, or inassociation with a water-soluble physiologically innocuous carrier, andare included within the scope of this invention. Examples of theseconcentrates are:

l. Mixtures of the active ingredient with a wetting, dispersing,thickening or gelling agent or a combination of such agents with orwithout a watersoluble physiologically innocuous carrier, e.g. wa-

ter;

2. Powders comprising the active ingredient, a physiologically innocuouscarrier, and a wetting, suspending or dispersing agent;

3. Stable dispersions obtained by mixing concentrates of types (1 or (2)with water; and

4. Mixtures of the active ingredient with a watersoluble physiologicallyinnocuous carrier, eg. sucrose or glucose.

Suitable dispersing agents include ethylene oxide/- glyceride oilcondensates, ethylene oxide/fatty alkylamine condensates andpolyoxyethylene(20)sorbitan monooleate. Suitable thickening agentsinclude sodium carboxymethylcellulose and water-soluble gums, e.g. gumtragacanth. Finely divided attapulgite clays may be used as gellingagents.

It is also possible to administer the anti-coccidial agents of thepresent invention orally to chickens in the form of granules, pellets,suspensions, solutions and emulsions comprising the active ingredient inassociation with suitable physiologically innocuous carriers andadjuvants. Such administration is, however, generally less convenientand therefore such compositions are not preferred.

Concentrates for addition to chicken feed generally contain from about 1percent to about 90 percent by weight of the active ingredient andpreferably about 4-50 percent by weight absorbed on or mixed with acarrier. Feedstuffs generally contain between about 0.0025 percent andabout 0.05 percent, more especially between about 0.00625 percent andabout 0.025

percent, of active ingredient by weight of the food consumed. Suchrelatively small amounts may be conveniently incorporated in the normalration prior to feeding the chickens.

The compositions of the invention may, with advantage, also contain oneor more additional prophylactic or therapeutic agents, for examplefurazoiidone or other anti-coccidial agents such as l-(4-amino-2-propyl-S-pyrimidinylmethyl)-2-picolinium chloride hydrochloride(amprolium sulphanilamidoquinoxaline (sulphaquinoxaline), 5-nitro-2-furaldehyde semicarbazone (nitrofurazone),quinoline-3-carboxylate anti-coccidial agents, e.g. ethyl6,7-diisobutoxy-4-hydroxyquinoline-3- carboxylate (buquinolate), ethyl6-n-decyloxy-7- ethoxy-4-hydroxyquinoline-3-carboxylate (decoquinate)and methyl 7-benzyloxy-6-n-butyl-4- hydroxyquinoline-3-carboxylate(methyl benzoquate), and3,5-dichloro-2,6-dimethyl-4-pyridinol(clopidol),2--methyl-3,5-dinitrobenzamide (zoalene),1,3-bis(pchlorobenzylidinamino)-guanidine (robenidine), monensin andethyl 2-{2,3-dimethyl-2-[4-( 3-pyrrolidin-l ylpropyl )thiosemicarbazonojethylidene} hydrazinecarbodithioate.

Also they may contain other substances known to be useful asantibacterial agents and in promoting the growth of poultry or their eggproduction such as, for example, 4-hydroxy-3-nitrophenylarsonic acid,l,5- bis( S-nitro-Z-furyl l ,4-pentadien-3one amidinohydrazonehydrochloride (nitrovin), zinc bacitracin and virginiamycin.

The following Examples illustrate compositions according to the presentinvention.

EXAMPLE 1 3',5-Dinitroacetanilide (5 parts by weight) was added to wheatflour (20 parts by weight). The mixture was ground and incorporated in asuitable feedstuff for chickens to give a final concentration of about0.0125 percent w/w of 3',5'-dinitroacetanilide. The treated foodstuffwas suitable for feeding to chickens to prevent coccidiosis.

Similar compositions may be prepared by replacing the3',5'-dinitroacetanilide by 3',5'-dinitroformanilide or by 3 ,5-dinitropropionanilide.

EXAMPLE 2 3,5'-Dinitro-N-methylacetanilide (5 parts by weight) was addedto wheat flour (20 parts by weight). The mixture was ground andincorporated in a suitable feedstuff for chickens to give a finalconcentration of about 0.0l percent w/w of 3,5-dinitro-N-methylacetanilide. The treated foodstuff was suitable for feeding tochickens to prevent coccidiosis.

Similar compositions may be prepared by replacing the3,5-dinitro-N-methylacetanilide by any other of the compounds of fonnulal.

The compounds of general formula l wherein R, R and R" are ashereinbefore defined, with the exception of 3',5'-dinitroformanilide,3',5'-dinitroacetanilide and 3',5.-dinitropropionanilide, are novelcompounds which have not hitherto been disclosed in the literature. Thepresent invention accordingly provides, as a feature of it, new3,5-dinitroaniline derivatives of the general formula:

wherein R" R and R" have the meanings hereinbefore specified in relationto symbols R, R and R respectively, R" being a methyl or ethyl groupwhen R" is a hydrogen atom and R is a hydrogen atom or a methyl or ethylgroup.

The disclosures in the literature of 3',5'- dinitroformanilide,3',5'-dinitroacetanilide and 3,5dinitropropionanilide do not mentiontheir useful activities against coccidia, but they do mentionassociations of these three compounds with water and with ethanol.Accordingly, veterinary compositions which are associations of either3',5-dinitroformanilide, 3',5'-dinitroacetanilide or3',5'-dinitropropionanilide with either water or ethanol alone areoutside the scope of the present invention.

The literature also discloses certain associations of3,5'-dinitroformanilide, 3',5'-dinitroacetanilide and3',5"dinitropropionanilide with substances which are not normallysuitable for use as carrier in a veterinary composition, i.e. aceticanhydride, acetic acid, diethyl ether, alkyl halides, ligroin, methanol,potassium hydroxide, sulphuric acid, nitric acid, and bromine.

As a further feature of the present invention, the novel compounds ofgeneral formula II are prepared by the acylation of compounds of thegeneral formula:

R" NH I Rli' lll wherein R" and R" are as hereinbefore defined.

'Generally the acylation is effected by the action of a compound of thegeneral formula:

R COR" lV [wherein R is as hereinbefore defined and R represents ahydroxy group or, when R represents an alkyl or cycloalkyl group, Rpreferably represents a halogen (eg. chlorine or bromine) atom or agroup OOCR R being as hereinbefore defined in respect of general formulaII ]optionally in the presence ofa solventv When R" and R in thestarting materials of general formula Ill represent hydrogen atoms, itwill be appreciated that R in general formula [V will be other than ahydrogen atom or a methyl or ethyl group as otherwise the3,5-dinitroaniline products would not conform to general formula II.

When R represents a hydroxy group or a group OOCR the reaction ispreferably carried out in the presence of a strong mineral acid, forexample a catalytic quantity of concentrated sulphuric acid. When Rrepresents a halogen atom, the reaction is preferably carried out in thepresence of a base, for example an aqueous alkali metal hydroxide (e.g.aqueous sodium hydroxide), or a tertiary amine (e.g. pyridine ortriethylamine) which may also act as solvent medium.

As a further feature of the present invention, the novel compounds ofgeneral formula ll wherein R" represents an alkyl group are prepared byN-alkylation of compounds of the general formula:

wherein R and R" are as hereinbefore defined.

Generally the alkylation is effected by the action of a compound of thegeneral formula:

(wherein R" represents a methyl, ethyl, n-propyl. isopropyl, n-butyl,iso-butyl or sec-butyl group, and X represents the acid residue of areactive ester, for example a halogen, e.g. iodine, bromine or chlorine,atom or a sulphuric or sulphonic acid residue) optionally in thepresence of a solvent, for example dimethylformamide or an alkanolhaving at most 4 carbon atoms, e.g. methanol, or in the presence of abase and a solvent, for example in the presence of sodium in liquidammonia or of an alkali metal carbonate in dimethyl sulphoxide. Thereaction is generally carried out at a temperature between 8()C. and +Cpreferably between 40C. and +3()C.

As a still further feature of the present invention, the novel compoundsof general formula ll, wherein R" represents a hydrogen atom, Rrepresents an alkyl group containing from l to 4 carbon atoms or acycloalkyl group containing 3 or 4 carbon atoms, and R represents ahydrogen atom or a methyl or ethyl group, R being a methyl or ethylgroup when R is a methyl or ethyl group, are prepared by effecting theBeckmann rearrangement of compounds of the general formula:

(wherein R and R are as immediately hereinbefore defined in respect ofgeneral formula ll, and R represents a hydrogen atom, a straightorbranchedchain alkyl or alkanoyl group containing up to 6 carbon atoms,or an arylsulphonyl group, eg a benzenesulphonyl or p-toluenesulphonylgroup). When R in the starting materials of general formula VI]represents a methyl or ethyl group, R must be a methyl or ethyl group inorder to obtain a new 3,5-dinitroaniline product conforming to generalformula ll. Conditions suitable for effecting the Beckmann rearrangementof ketoximes to amides in general are well known in the .art and aredescribed, for example, in the review by pentachlorlde or concentratedsulphuric acid, usually in the presence of an organic solvent such asdiethyl ether at a temperature between C. and l(lC.

Compounds of general formulae Ill, IV, V, Vl and Vll may be prepared bythe application or adaptation of well-known methods, that is to saymethods hitherto used or described in the literature.

The following Examples illustrate the preparation of novel compounds ofthe present invention.

EXAMPLE 3 iso-Butyryl chloride (6.3 ml.) was added dropwise during l5minutes to a stirred solution of 3,5- dinitroaniline (5.5 g.) in amixture of dimethylformamide (18 ml.) and dry pyridine (18 ml.)maintained at a temperature of ()-5C. The reaction mixture was allowedto warm to room temperature during 30 minutes and then added to amixture of ice and water (200 ml.). The precipitate was filtered off,dissolved in dimethylformamide (50 ml.) and added to a mixture of iceand water (300 ml.) containing concentrated hydrochloric acid ml. Theprecipitate was filtered off, washed with saturated aqueous sodiumbicarbonate solution and then with water and dried. Crystallisation fromaqueous ethanol gave 3',5'-dinitro-isobutyranilide (5.6 g. m.p. l65l68C.

By proceeding in a similar manner, but substituting n'butyryl chloridefor the iso-butyryl chloride used as starting material, there wasprepared 3,5'-dinitro-nhutyrylanilide m.p. 97-98C. By again proceedingin a similar manner, but using 3,5-dinitro-Z-methylaniline in drytetrahydrofuran in place of the 3,5-dinitroaniline in dimethylformamideand acetyl chloride in place of the butyryl chloride, there was prepared3',5-dinitro 2methylacetanilide, m.p. l57-l59C.

The 3,5-dinitro-Z-methylaniline used as a starting material was preparedas follows Chloroform (38 ml.) was added carefully to a stirred mixtureof oleum l6.9 ml.: 20 percent free sulphur trioxide) and concentratedsulphuric acid (3.8 ml.) followed by 3,S-dinitro-Z-methylbenzoic acid(l().0 g.). The mixture was warmed to 45C. and sodium azide (3.28 g.)was added in small portions over 20 minutes, the temperature of thereaction mixture being kept between 45 and 50C, by means of intermittentcooling. After the addition was complete, the mixture was stirred andheated under reflux for one hour on the steam bath and then thechloroform was removed by decantation and the residue was poured intoice-water (300 ml. The yellow precipitate was filtered off, washed withwater and dried, to give crude 3,5-dinitro- Z-methylaniline (8.8 g.),m.p. l67 l7lC. The crude product was dissolved in ethyl acetate, washedwith saturated aqueous sodium bicarbonate solution and then with waterand the solvent was removed in vacuo. Trituration with petroleum ether(b.p. 40-60C.) gave 3,5-dinitro-2-methylaniline (7.5 g. m.p.l72.5-l74.5C.

EXAMPLE 4 A mixture of 3,5-dinitroacetanilide (6.76 g.), anhydrouspotassium carbonate (6.22 g. methyl iodide (2.82 ml.) and drydimethylsulphoxide (27 ml.) was stirred for 18 hours at room temperaturein a stoppered flask. The reaction mixture was then diluted with water150 ml.) and allowed to stand for a few minutes. The crystalline solidwas filtered off and washed with water.

The solid was recrystallised from a mixture of petroleum ether (b.p.6080C.) and benzene, and then from ethanol, to give3',5'-dinitro-N-methylacetanilide (2.53 g.), m.p. l34.5-l36C.

EXAMPLE 5 A stirred suspension of N-n-butyl-3,S-dinitroaniline (5.5 g.)in acetic anhydride (20 ml.) was treated with a few drops ofconcentrated sulphuric acid and then heated on the steam bath for 3hours. The cooled reaction mixture was added to-ice-water (400 ml.) andthe product was extracted with ethyl acetate (3 X lOO ml. The combinedorganic extract was washed with 2N aqueous sodium bicarbonate solution,dried with anhydrous magnesium sulphate. and the solvent removed invacuo, to give 3,5'-dinitro-N-n-butylacetanilide (2.8 g.), in the formof an amber syrup, vl670 cm".

EXAMPLE 6 Sodium hydride (50 percent in mineral oil; 1.44 g.), followedby ethyl iodide (3.6 ml. were added, in small portions during 2 minutes,to a warm stirred solution of 3',5-dinitroacetanilide (6.75 g.) indimethylformamide (20 ml.). The mixture was heated on the steam bath for150 minutes, then cooled, poured into water (400 ml.) and extracted withethyl acetate (3 X ml. The combined organic extracts were washed withwater, dried over anhydrous magnesium sulphate and evaporated todryness. The residue was purified by chromatography on alumina 150 g.)using benzene as the eluant. The fractions containing the requiredproduct were combined, evaporated to dryness and the residuecrystallised from ethanol, to give 3,5'-dinitro-N- ethylacetanilide (4.2g.), m.p. l26l27C.

By proceeding in a similar manner, but substituting n-propyl iodide forthe ethyl iodide, there was prepared 3,5-dinitroN-n-propylacetanilide,m.p. 98-lOOC.

EXAMPLE 7 Methyl iodide (21.4 g.) was added to a mixture of3,5-dinitroformanilide 19.0 g.) and anhydrous methanol ml.), and themixture was heated under reflux for 2 hours. The mixture was poured intoice-water and the deep orange precipitate was filtered off.Crystallisation from methanol gave 3,5-dinitro-N-methylaniline, m.p. l53l54C., as a by-product. The mother liquors from the crystallisationwere evaporated to small bulk, glacial acetic acid 100 ml.) was addedand the solution was poured into ice-water (200 ml.). The precipitai:was filtered off and discarded. The filtrate was treated with anhydroussodium carbonate. The pale yellow flocculent precipitate was filteredoff and crystallised from methanol, to give 3',5'-dinitro-N-methylformanilide (2 g.), m.p. 93-94C.

EXAMPLE 8 A mixture of 3,5-dinitroaniline (5.0 g.),cyclopropane-carboxylic anhydride (15 ml.) and two drops of concentratedsulphuric acid was warmed on the steam bath for 5 minutes and thenallowed to stand for 2 hours at r om temperature. The reaction mixturewas diluted with diethyl ether (200 ml.), the colourless crystallineprecipitate was filtered off, and crystallised from methanol containinga small amount of water, to give 3,5'-dinitrocyclopropanecarboxanilide(2.8 g.), m.p. l47 -l4 EXAMPLE 9 A mixture of formic acid (10 ml.) andacetic anhydride ml.) was stirred at room temperature for 30 minutes.N-methyl-3,S-dinitroaniline (5.0 g.) was then added and the reactionmixture was heated on a steam bath for minutes. The mixture was allowedto cool to room temperature during 40 minutes, then poured intoice-water and the precipitate was filtered off. Recrystallisation frommethanol gave 3'.5'-dinitrol\'- methyl-formanilide (2.2 g.), m.p. 9394(.

The following Procedures illustrate the preparation of compounds ofgeneral formula I which have been hitherto described in the literature.

PROCEDURE 1 of ethanol and water (2:1 by volume) gave 3'.5'

dinitroacetanilide (11.5 g.) in the form of colourless By proceeding ina similar manner, but substituting n-propionic anhydride for the aceticanhydride used a starting material, there was prepared3',5'-dinitropropionanilide, m.p. l59-160C.

PROCEDURE 2 Acetic anhydride (6.0 ml.) was added to formic acid (98l00percent w/v; 24.0 ml.) with swirling and cooling and the mixture wasallowed to stand at room temperature for 30 minutes. 3,5-Dinitroaniline(6.0 g.) was then added. The reaction mixture was warmed for 5 minuteson the steam bath and allowed to stand for 40 minutes, allowing it tocool to room temperature. Water 100 ml.) was added, and the precipitatewas filtered off and dried. Crystallisation from a mixture of petroleumether (b.p. 6080C.) and ethyl acetate (2:1 by volume) gave3',5'-dinitroformanilide (4.1 g.), m.p. l2l-123C.

PROCEDURE 3 Phosphorus pentachloride (1.0 g.) was added to a stirredsolution of 3',5 '-dinitroacetophenoxime 1.0 g.) in dry diethyl etherml.) at about 5C. The temperature of the mixture was allowed to rise toabout C. over 1 hour, and then dry acetonitrile 10 ml.) was added andthe temperature of the mixture was raised to 35C. for 15 minutes. Themixture, after cooling, was added to ice-water (50 ml.) and allowed tostand for a few minutes. The product was extracted with chloroform (3 X50 ml.), and the combined organic extracts were dried over anhydrousmagnesium sulphate and evaporated to dryness in vacuo. The residue waspurified by passage through an alumina column (20 g.) using ethylacetate as eluant. The purified solution (300 ml.) was evaporated todryness and the residue crystallised from ethanol, giving 3 ,5dinitroacetanilide (0.43 g.), m.p. 189l9lC.

We claim:

1. A 3,5-dinitroaniline derivative of the formula:

NO, Mo

wherein R" is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl or sec-butyl, R is hydrogen, alkyl of 1 through 4 carbon atomsor cycloalkyl of 3 or 4 carbon atoms, and R is hydrogen, methyl orethyl, R being methyl or ethyl when R" is hydrogen and R is hydrogen,methyl or ethyl.

2. A 3.5-dinitroaniline derivative according to claim 1 wherein R" ismethyl, ethyl, n-propyl. iso-propyl. n-butyl, iso-butyl or sec-butyl.

3. A 3,5-dinitroaniline derivative according to claim 1 wherein R ismethyl or ethyl.

4. The 3,5-dinitroaniline derivative according to claim 1 which is3',5'-dinitro-iso-butyranilide.

S. The 3,5-dinitroaniline derivative according claim 1 which is3',5'-dinitro-n-butyrylanilide.

6. The 3,5-dinitroaniline derivative according claim 1 which is3',5-dinitro-2'-methylacetanilide.

7. The 3,5-dinitroaniline derivative according claim I which is3',5'-dinitroN-methylacetanilide.

8. The 3,5-dinitroaniline derivative according claim 1 which is3',5'-dinitroN-n-butylacetanilide.

9. The 3.5dinitroaniline derivative according claim 1 which is3,5'-dinitro-N-ethylacetanilide.

10. The 3,5-dinitroaniline derivative according to claim 1 which is3',5-dinitro-N-n-propylacetanilide.

11. The 3,5-dinitroaniline derivative according to claim 1 which is3',5'-dinitro-N-methylformanilide.

12. The 3,5-dinitroaniline derivative according to claim 1 which is3',5'-dinitrocyclopropanecarboxanilide.

1. A 3,5-DINTROANILINE DERIVATIVE OF THE FORMULA:
 2. A3,5-dinitroaniline derivative according to claim 1 wherein R1 is methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or sec-butyl.
 3. A3,5-dinitroaniline derivative according to claim 1 wherein R3 is methylor ethyl.
 4. The 3,5-dinitroaniline derivative according to claim 1which is 3'',5''-dinitro-iso-butyranilide.
 5. The 3,5-dinitroanilinederivative according to claim 1 which is3'',5''-dinitro-n-butyrylanilide.
 6. The 3,5-dinitroaniline derivativeaccording to claim 1 which is 3'',5''-dinitro-2''-methylacetanilide. 7.The 3,5-dinitroaniline derivative according to claim 1 which is3'',5''-dinitro-N-methylacetanilide.
 8. The 3,5-dinitroanilinederivative according to claim 1 which is3'',5''-dinitro-N-n-butylacetanilide.
 9. The 3,5-dinitroanilinederivative according to claim 1 which is3'',5''-dinitro-N-ethylacetanilide.
 10. The 3,5-dinitroanilinederivative according to claim 1 which is3'',5''-dinitro-N-n-propylacetanilide.
 11. The 3,5-dinitroanilinederivative according to claim 1 which is3'',5''-dinitro-N-methylformanilide.
 12. The 3,5-dinitroanilinederivative according to claim 1 which is3'',5''-dinitrocyclopropanecarboxanilide.